Transcript Document

Menopause & HRT
Amr Nadim, MD
Professor of Obstetrics & Gynecology
Ain Shams Faculty of Medicine
[[email protected]]
POSTMENOPAUSAL
WOMEN’S HEALTH
Amr Nadim, MD
Professor of Obstetrics &Gynecology
Ain Shams Faculty of Medicine
Objectives
• Understand major health issues facing
postmenopausal women
• Understand the results of RCT’s of estrogen
and how they differ from observational
studies
• Learn about alternative therapies for postmenopausal women.
Menopause
• Cessation of menstrual
periods due to declining
estrogen and progesterone
production by the ovaries
• Refers to the final menstrual
period – must be free of
periods for one year to be
called menopause
Stages of Menopause
Premenopause
Menopause
Climacteric
Post-menopause
• Natural Menopause
– Early and Premature menopause
– Premature ovarian failure
• Induced Menopause
TYPES
• Natural Menopause
diagnosis is established
when menstruation stops for
12 months in the absence of
an organic or a pathological
cause.
–
This usually occurs at the
age of 45-50 years.
–
If it occurs before the age of
40 years, it is referred to as
“Premature Menopause”.
• Induced Menopause
May be:
• Surgical after bilateral
oophorectomy
• Radiological after irradiation of
the ovaries
• Chemotherapeutic after
exposure to chemotherapy
during treatment of malignant
diseases
PATHO-PHYSIOLOGY
a) Endocrine Changes:
The squeal of endocrine changes is as follows:
• Decrease in inhibin production by the ovary.
• Decrease in oestradiol blood level.
• Increase in follicle stimulating hormone (FSH) production by the
pituitary gland (> 30 lU/ml).
• Increase in lutenizing hormone (LH) production.
• The menstruation may stop abruptly but more commonly after a
period of oligo and/or hypomeorrhoea.
• During this climacteric period, bleeding from a proliferative
endometrium (because of anovulation) may be irregular and
acyclic.
– In such cases, endometrial carcinoma should be excluded before
attributing it to hormonal changes.
Hormonal Pattern after Menopause
• A state of gradual Estrogen Deprivation
• FSH and LH
• Androgens
The Menopausal Syndrome
Key Public Health Issues for Postmenopausal
Women
– Heart disease
– Osteoporosis
– Cancer
– Dementia
Other Key Health Issues:
– Postmenopausal Symptoms –
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Menstrual irregularities,
Vaginal dryness,
Hot flashes
Diminished libido
– Urinary Issues –
• Incontinence, frequency
chronological
biological
Menopause
psychological
physiological
cultural
The Golden Rule Is :
•Always try to be empathetic and
NEVER underestimate your patient
complaints
•Avoid telling her about a complaint:
“It will take its time and fade away”
Symptoms of Menopause
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Irregular menses
Hot flashes
Vaginal dryness
Urinary incontinence
Loss of Libido
Hot Flashes
What are they…?
• Sudden rush of heat to upper body, followed by
sweating and chills.
• Preceded by a prodrome of palpitations and
pressure within the head.
• A vasomotor “FLUSH” affecting the upper
thorax, neck and face may be objectively
demonstrated.
• Affect 50 to 85% women at some point:
– 85% for > 1 year
– 25-50% for up to 5
• 15% find them troubling and interfering
with their life:
– Poor quality of sleep, irritability, chronic
fatigue.
– Public embarassement
• 20% have more than one attack /day
– Seasonal variations
– Tend to occur by night
• More in Slim women who smoke
Etiology
• Thermoregulatory and Vasomotor
Instability
– involving α-adrenergic mechanisms and
endogenous opioid peptides.
– The Hypothalamic thermostat is reset at a
lower set-point
• Triggered by hormonal changes:
– Estrogen Withdrawal rather tan
hypoestrenemia
– Pulsatile LH release
– DHEA, Androstenedione, ACTH, β-lipotropin
and β-endorphin.
Estrogen
Increase Intraneuronal
NE release
Inhibits NE re-uptake
Increase Hypothalamic
α2 postsynaptic receptors
Estrogen Withdrawal seems to act through reducing α2 adrenergic
Activity ERT must be given for 2-4 weeks before achieving optimal effect
because Action involves central pathways
Management
•
Estrogen
– Effectively stops hot flashes
– Hot flashes return as soon as ERT is withdrawn
– Tapering Estrogen dose over several week is
advisable.
• Progestins
– 10 mg Provera, 150 mg DMPA
– Reseting of the hypothalamic thermostat at a higher set
point.
– Side-effects
• Clonidine (Catapress)
– Stabilizes the thermoregulatory mechanisms
– 0.1 to 0.2 mg twice daily
– Rarely used because it relieves HF by only 30 % (a little different
from placebo)
• Veralipride( Agrèal®)
– 100mg daily for 20 days/month
– Antidopaminergic
– Side effects
• Herbs
– Phytoestrogens: Soy flour, Ginseng black
Cohash
• Home remedies:
– Dress in light layers; small fan to cool the face;
light bedclothes and cotton blanket
– Avoid alcohol and caffeine.
Vaginal Dryness
• Definition: reduced vaginal secretions and
thinning of the mucous membranes lining the
vagina  dryness, itching, and painful
intercourse
• Cause and pathophysiology:
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Declining estrogen levels
Lowered vaginal acidity
The vagina becomes shorter, narrower and inelastic
The vaginal skin becomes brittle, thin and vulnerable to
infection.
• Diagnosis
– Clnical examination
– Low KPI
Management
• Treatment:
– Topical estrogens:
• Premarin®
• Ovestin ®
– nonprescription lubricant such as Astroglide®
• Home remedies: regular sexual activity or
vegetable oils
Urinary Issues
• Complaints
– Incontinence:
• Stress or urge incontinence
• Recurrent urethritis
• Cause: declining estrogen levels  thinning of
urethra and bladder tissue; anatomical changes in
pelvic organs such as cystocele, rectocele or
uterine prolapse
• Treatment: varies by cause; estrogen therapy may
improve bladder control
• Other remedies: Kegel exercises; avoid caffeine,
alcohol, and high dose Vit C; bladder retraining
Sexual Issues
• Declining libido has been long considered
a companion of climacteric and
postmenopause.
• Is this true?
Skin Collagen
• After menopause:
– 2.1% of the skin collagen are lost per year
– Up to 30% are sometime lost in the first 5
years.
• Estrogen
– Improves both amount and quality of Collagen
– Improves skin hydrophilic capacities
– Reduces wrinkles
• Other alternatives
– Moisturizing preparations
– Primrose oil
Body Weight Issues
• Normal Circulating estrogen levels directs
fat distribution to gynecoid fat areas.
• After menopause fat is redirected to a
rather android distribution (an
independent risk factor for heart disease).
• ERT:
– Does NOT cause weight loss or gain
– Positively affect body fat distribution.
HRT …
Estrogen…Is a Miracle Drug
• Estrogen works for hot flashes and
vaginal dryness
• May help with urinary incontinence
• All types and routes of administration
equally effective
• Markedly improves quality of life for
younger postmenopausal women
What If…
• Contraindication to HRT
• Belief that HRT interfere with nature
• Desire to be in control
• Fear of long term effects of HRT
• Fear of adverse effects.
• lack of information about HRT
Alternatives…
• Lifestyle Changes
• Dietary changes & supplements
• Complementary therapies
• Drugs
Estrogen and Heart Disease
• A healthy 60 year old female has about a 30%
lifetime risk of dying of heart disease
• Observational studies show a 35 to 50% lower
risk of CAD in estrogen users
• However, results of recent clinical trials conflict
with these findings
Why the Differences Between
Observational Studies and RCTs for CAD?
• OS may produce the wrong answer if there are
unmeasured differences between hormone users and
nonusers
• Women who take HRT are generally healthier and
wealthier than nonusers (some studies did not adjust
for SES)
• Adherence has been shown to be a strong marker for
low risk of coronary events.
• Issue of 1º versus 2º prevention of CAD
• Randomization helps eliminate these and other
potential biases
HERS Conclusions
• Treatment with HRT did not reduce the
overall rate of CHD events in
postmenopausal women
• HRT not recommended for secondary
prevention
Collaborative Group on Hormonal
Factors in Breast Cancer
Analyses based on 53,865 postmenopausal
women, 33% of whom had ever used HRT
• RR 1.35 for > 5 yrs HRT use
• RR ~ 1.0 if < 5 yrs since HRT use
• Ever HRT users had tumors that were less
advanced clinically
• Effect on mortality unclear
Lancet 1997
WHI Estrogen+Progestin Trial
Specific Aims
• To test whether E+P:
• Reduces the incidence of CHD and other
CVD
• Reduces the incidence of all osteoporosisrelated fractures and hip fractures separately
• Increases the risk of breast cancer
Profile of the Women’s Health Initiative Randomized Trial of
Estrogen Plus Progestin in Women With an Intact Uterus
Initiated screening (N = 373,092)
Provided consent and reported
no hysterectomy (N = 18,845)
Randomized (N = 16,608)
Estrogen +Progestin
(N = 8,506)
Status on 4/30/02
 Alive/outcomes data
submitted in last 18
months (n = 7,968)
 Unknown vital status
(n = 307)
 Deceased (n = 231)
Placebo
(N = 8,102)
Status on 4/30/02
 Alive/outcomes data
submitted in last 18
months (n = 7,608)
 Unknown vital status
(n = 276)
 Deceased (n = 218)
Attributable Risk Summary
• Excess risk per 10,000 person-years on E+P
– 7 more women with CHD
– 8 more women with stroke
– 8 more women with PE
– 8 more women with breast cancer
• Risk reduction per 10,000 person-years on E+P
– 6 fewer colorectal cancer
– 5 fewer hip fractures
• Summary: 19 additional monitored events per 10,000
person years on E+P
WHI Estrogen+Progestin Trial
Summary
• Treatment with estrogen plus progestin for up to 5
years is not beneficial overall.
• There is early harm for CHD, continuing harm for
stroke and VTE, and increasing harm for breast
cancer.
• This risk-benefit profile is not consistent with a
viable intervention for primary prevention of
chronic diseases in postmenopausal women.
WHI Estrogen+Progestin Trial
Implications
• Estrogen plus progestin should not be
initiated or continued for the primary
prevention of CHD.
• The risks for CHD, stroke, PE and breast
cancer must be weighed against the benefit
for fracture in selecting from the available
agents to prevent osteoporosis.
Why Alternatives to HRT are requested?
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Contraindication to HRT
Belief that HRT interfere with nature
Desire to be in control
Fear of long term effects of HRT
Fear of adverse effects.
Lack of information about HRT
Facts about alternatives for HRT
1.Most treat only a single problem
2.There is potential harm, because of a lack
of efficacy or possible risks
3.There is a lack of evidence to confirm
benefits or possible adverse effects.
4.There is a widespread belief that “natural”
means harmless, but herbs may contain
potent chemicals & should be used with
caution.
Alternatives to HRT
•
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•
Lifestyle Changes
Dietary changes & supplements
Complementary therapies
Drugs
Life Style Changes
• Avoidance of Triggers for Vasomotor
Changes
• Avoidance of Risk Factors for
osteoporosis
• Exercise
Multivitamins
• Vit E: 400-1200 IU daily
– Reduces VM symptoms (KassAnnesse,2000)
– Reduces the risk of CHD (100 IU daily for 2
years)
– Low level of Vit E is a better predictor of CHD
than elevated cholesterol or blood pressure
(Cooper et al,1994)
• Vitamin D: 400 IU daily with calcium
significantly reduced fracture risk (Chapuy
et al, 1992)
• Oily fish eaten at least twice a week
reduced mortality from CHD (Daviglus et
al, 1997)
• Garlic: reduction of cholesterol is doubtful
(Daviglus et al, 1997)
Minerals
• Adequate calcium intake: 1500 mg daily:
reduction of hip fracture (Cumming et al, 1997).
• Adequate intake of magnesium is crucial for
osteoporosis prevention (Kass-Annesse,2000).
• The dietary ratio of calcium to magnesium is
best maintained at 2:1.
•
Selective Estrogen Receptor
Modulators (SERM)
SERMs are compounds that engage the estrogen receptors
and
– exert estrogen agonist effects in desired target tissues such as
bone and the cardiovascular system
– together with estrogen antagonism (or clinically neutral effect) in
the reproductive tissues such as the uterus and breast. this is
differential activity in human tissues.
– Tamoxifen: Is a first generation SERM.
– Raloxifen: Is a benzothiophene derivative and comes closer to be
the ideal estrogen.
• It displayes activity against breast cancer comparable to tamoxifen,
selectivity inhibited uterine tissues, and simultaneously maintained
bone density and favorable serum lipid profile,
• yet failed to control postmenopausal vasomotor symptoms and even
may exagerate them..
Tibolon
•
Tibolon is a steroid with tissue-specific activities which
has the capacity to exert estrogenic or
progestogenic/androgenic effects, depending on the
tissue substrate.
• These tissue-specific properties of tibolon enable it to act
in specific parts of the body like an estrogen:
– Providing effective relief of climacteric symptoms.
– Preventing osteoporotic bone loss.
– Having beneficial androgenic effects on mood and libido.
• Tibolon has the following advantages:
– On the endometrium: It does not act as an estrogen. Therefore
does not stimulate endometrial proliferation. In contrast to
conventional HRT, the use of Tibolon does not require the
addition of a progestogen to induce regular withdrawal bleedings
to limit endometrial proliferation, nor to protect against
endometrial hyperplasia.
– On the breast tissue: It does not act as an estrogen in breast
tissue. This leads to low incidence of breast tenderness and
causes no increased mammographic density.
Avoid factors increasing urinary calcium loss
• High sodium intake
• High phosphorus (soft drinks such as
cola) & may be damaging for young bone
(Carey & Carey, 1999).
• High protein intake, generally in the form
of animal protein (Nordin, 2000).
• High caffeine intake is associated with an
increase in fracture
Natural hormones
A. Phytoestrogens [Derived from plants ]
– Asian women experience fewer menopausal symptoms
than western women & their traditional diet contain high
level of phytoestrogens, about 200 mg daily compared
with < 5 mg daily in western diet.
• Types
– Isoflavones: soya beans (richest source), chick peas,
lentils
– Lignans: apples, stone fruits, onion, garlic, seed oils,
cereals, fruit & vegetables.
– Coumestans: clover
• Available in:
– tablet (Klimadynon=cimicifugae)
– food supplements in bread,
– snack bars,
– health drinks.
Natural progestagen creams
• Extracted from: plant source, mainly yams
& soya.
• Effects: An improvement in vasomotor
symptoms but no effect on bone
Dehydroepiandrosterone (DHEA)
• Available as: a food supplement.
• Effects:
– improved mood, sleep, tiredness & ability to
cope (Thaker & Booher, 1999).
• Adverse effects:
– lowering HDLP, increasing insulin resistance
& raising blood pressure
Complementary Therapy
•
•
•
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Herbalism.
Acupuncture.
Stress reduction.
Homoeopathy
Herbalism:
[There is a widespread belief that “natural” means harmless, but herbs may contain
potent chemicals & should be used with caution]
• Black cohosh (Cimmicifugae racemosae)
– Effective in alleviation of vasomotor symptoms,
insomnia & low mood (Mckenna et al, 2001).
– Daily dose: 40 mg & no longer than 6 months.
– No drug interaction.
• St John s Wort (Hypericum)
– Dose: 900 ug daily.
– Effective in reducing flushes, low mood, insomnia
(Grube et al, 1999).
– Drug interactions include: theophylline, digoxin,
cyclosporin, combined oral contraceptive pills.
• Valerian, sage, chste tree, dong quai,
ginseng, gingko biloba, kava, garlic, &
feverfew: Comission E does not recommend
them for use at menopause (2002) because
of Limited scientific data or adverse side
effects.
• Oil of evening primrose in a placebo RCT is
not effective (Chenoy et al, 1994)
• Chinese herbs are not effective in placebo
RCT (Davis et al, 2001)
For prevention & treatment of
osteoporosis
• Bisphosphonates
– Alendronates: Fosamax
– Residronates: Actonelle
• Raloxifene and other SERMs
– Evista
• Tibolone: Livial
For treatment of vasomotor symptoms
•
Antidepressants:
– For hot flushes. Also positive effect on mood & libido,
– Adverse effects: dry mouth, nausea, constipation, & reduced appetite
• Paroxetine (seroxat) (20 mg daily): 67% reduction in hot flushes (Stearns et al, 2000)
• Venlafaxine (Efexor) (75 mg daily): 61% reduction (Loprinzi, 2000) (RCT). The benefits are
seen within a couple of weeks.
• Venlafaxine 37.5 mg daily: 37% reduction of hot flushes & fewer adverse effects
•
Night sedation:
– For insomnia & mood swings
•
Veralipide (agreal):
– 100 mg daily for 20 days, repeated after 10 days. It is neuroliptic
•
Propranolol:
– No data to support its use (Brockie, 2002)
•
Bellergal-Retard:
– phenobarbitone (central sedative 40 mg), belladona (parasympathetic inhibitor, 0.2
mg), ergometrin tartarate (sympathetic inhibitor, 0.6 mg) one tab twice daily
•
Clonidine (catapress):
– 0.1 to 0.2 mg twice daily
– Rarely used because 30 % reduction which is little different from placebo (Laufer,
1982)
•
Gabapentin (Guttuso, 2000). (Uncontrolled study)
For symptomatic treatment of
atrophic vaginitis
• Simple vaginal lubricants:
– Astroglide, Lubrin, replens
• Long acting bioadhesive vaginal moisturiser:
– It is comparable to vaginal estrogen preparation
(Nachtigal,1994).
– It is a gel containing water & polycarbophil that adhere to
the vaginal wall, encouraging water back into the
dehydrated cells. Each application lasts for about 3 days.
• Vaginal estriol or estradiol:
– It is not absorbed systemically to any significant degree.
– They can be used safely in women with a contraindication
to systemic estrogen .